A strong genetic basis for bipolar disorder has been demonstrated by family and twin studies, yet classical genetic linkage analyses have yet to define relevant loci. Thus, multiple genes, each conferring a moderate increase in risk may underlie susceptibility to this disorder. We propose using large-scale association studies (of the transmission disequilibrium design) to identify alleles conferring increased risk for bipolar disease. This approach is complementary to linkage analyses and takes advantage of data from linkage analyses. We hypothesize that certain areas which have yielded linkage signals in three or more whole genome scans may harbor disease alleles of moderate individual impact, but of large potential population impact. Thus, we will focus on genes/SNPs from these areas. Additionally, in selecting further genes for our association studies, we will take into account biochemical and mRNA expression studies that are beyond the scope of this grant, but which will likely identify additional interesting genes to genotype. Thus, triangulating on candidate genes using knowledge obtained from linkage analysis, biochemical and expression studies is a promising approach to identifying risk alleles for bipolar disease. We have developed a robust, inexpensive genotyping method, have gained access to extensive, patient-parent trios, will benefit from the analytical and informatics expertise of the Whitehead Institute Center for Genome Research and are therefore poised to proceed with a rationally designed, large-scale association study of bipolar disease which will include analyses of upwards of 2,000,000 genotypes.